Antovic Jovan P, Antovic Aleksandra
Coagulation Research, Department of Surgical Sciences, Karolinska Hospital, Stockholm, Sweden.
Thromb Haemost. 2003 Oct;90(4):620-7. doi: 10.1160/TH03-03-0168.
Using the recently developed overall hemostatic potential (OHP) assay, we investigated the effects of different concentrations of recombinant factor VIIa on overall hemostasis and on thrombin activatable fibrinolysis inhibitor (TAFI) dependent fibrinolysis in different factor deficient plasmas. rFVIIa increased OHP in FV, FVIII and FIX deficient plasmas but not up to the levels in normal pooled plasma (NPP). Maximal levels were found at 2.4 microg/mL of rFVIIa, while higher doses did not further increase OHP. In FXII deficient plasma, OHP is higher than in NPP and addition of rVIIa further increased it. Even very high concentrations of rFVIIa (9.6 microg/mL) did not induce a significant increase of OHP in NPP. Higher concentrations of rVIIa down-regulated fibrinolysis in FVIII, FIX and FXI deficient plasmas to values obtained in NPP. Using potato tuber carboxy-peptidase inhibitor (PTCI), a specific inhibitor of TAFI, it was found that TAFI's influence on fibrinolysis down-regulation in FVIII and FIX deficient plasmas increased after addition of higher concentrations of rFVIIa. From this in vitro study it seems that rFVIIa in a concentration of 2.4 microg/mL improves overall hemostasis in FV, FVIII and FIX deficient plasmas. rFVIIa, even at very high (supra-therapeutic) concentrations, does not induce hypercoagulability either in NPP or in deficient plasmas. Higher concentrations of rVIIa induce, at least partly, TAFI dependent down-regulation of fibrinolysis in FVIII and FIX deficient plasmas. These results, together with some previous ex vivo studies, point to OHP assay as a possible diagnostic tool for evaluating the hemostatic effects of rFVIIa.
利用最近开发的整体止血潜力（OHP）检测方法，我们研究了不同浓度的重组凝血因子VIIa（rFVIIa）对不同凝血因子缺乏血浆中整体止血以及对凝血酶激活的纤维蛋白溶解抑制物（TAFI）依赖性纤维蛋白溶解的影响。rFVIIa可增加FV、FVIII和FIX缺乏血浆中的OHP，但未达到正常混合血浆（NPP）中的水平。在rFVIIa浓度为2.4μg/mL时发现OHP达到最高水平，而更高剂量并未进一步增加OHP。在FXII缺乏血浆中，OHP高于NPP，添加rVIIa可使其进一步升高。即使是非常高浓度的rFVIIa（9.6μg/mL）也未在NPP中引起OHP的显著增加。更高浓度的rVIIa可将FVIII、FIX和FXI缺乏血浆中的纤维蛋白溶解下调至NPP中的水平。使用马铃薯块茎羧肽酶抑制剂（PTCI），一种TAFI的特异性抑制剂，发现添加更高浓度的rFVIIa后，TAFI对FVIII和FIX缺乏血浆中纤维蛋白溶解下调的影响增加。从这项体外研究看来，浓度为2.4μg/mL的rFVIIa可改善FV、FVIII和FIX缺乏血浆中的整体止血。rFVIIa即使在非常高（超治疗）浓度下，在NPP或缺乏血浆中也不会诱导高凝状态。更高浓度的rVIIa至少部分地诱导FVIII和FIX缺乏血浆中TAFI依赖性的纤维蛋白溶解下调。这些结果与一些先前的体外研究一起，表明OHP检测可作为评估rFVIIa止血效果的一种可能的诊断工具。
